TWI779064B - N-(2-(substituted-naphthalen-1-yl)ethyl) substituted amide compounds, their preparation and use - Google Patents

Abstract

The disclosure relates to N-(substituted naphthyl-ethyl) substituted amide compounds and their use as melatonin receptor agonists and 5-HT _2c receptor antagonists, specifically to compounds of formula I or their pharmaceutically acceptable Acceptable salts, solvates or mixtures thereof and pharmaceutical compositions thereof, wherein X, R ₁ , R ₂ are as defined herein.

Description

N-(2-(substituted-naphthalene-1-yl)ethyl) substituted amides, their preparation and use

The disclosure relates to N-(2-(substituted-naphthalene-1-yl)ethyl) substituted amide compounds and their preparation methods, pharmaceutical compositions and the prevention/treatment of melatoninergic system diseases, tension, anxiety, seasonal Methods and uses for diseases or conditions such as sexual affective disorder, cardiovascular disease, digestive system disease, schizophrenia, phobia, depression, major depression, sleep disorder, sleep disorder, insomnia or fatigue caused by jet lag, weight disorder, etc. .

Melatonin receptor (MT) agonists are a new class of compounds with antidepressant, anxiolytic, circadian cycle and body weight regulation effects. Compared with currently commonly used selective serotonin (5-HT) reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) antidepressants, melatonin receptor activation Drug-based compounds have multiple advantages in application, mainly less adverse reactions, including weight gain, adverse effects on sexual function, drug withdrawal reactions, etc. Due to its new mechanism of action and good clinical performance, this type of drug is currently attracting attention. At present, four drugs of this type have been listed, namely Melatonin, Agomelatine, Ramelteon, and Tasimelteon; Phase TIK301 study.

Agomelatine is the only melatonin receptor agonist antidepressant that has been approved for clinical use, developed by the French company Servier. Compared with other melatonin receptor agonists, agomelatine is particularly special. It is not only an agonist of melatonin receptors MT ₁ and MT ₂ (inhibition constants K _i are 6.15×10 ^-11 mol/L and 2.68×10 ^-10 mol/L, respectively), but also a 5-HT _2c receptor Antagonist (IC ₅₀ =2.7×10 ^-7 mol/L). A number of clinical studies have proved that it has an obvious antidepressant effect, has a rapid onset, and has good curative effect on depression and accompanying anxiety disorders; MDD) may be more effective in improving the continuity and quality of sleep in patients with MDD; at the same time, its negative impact on sexual function is significantly less than that of other antidepressants.

The drug was launched in Europe in 2009 and was approved for import in my country in April 2011. At present, its clinical indication is adult depression, and clinical research on anxiety and sleep disorders is also underway.

As a multi-target antidepressant with a new mechanism, agomelatine was positioned as a "blockbuster" new drug in the market before its launch, but the response after the launch was not as expected. The main reasons include its unsatisfactory in vivo metabolic properties and its adverse effects on liver enzymes.

The oral absorption of agomelatine is rapid and complete (more than 80%), but due to the first-pass effect of the liver, after absorption, it is metabolized by CYP1A2 (about 90%) and CYP2C9 (about 10%), through demethylation And hydroxylation reaction, eventually produce dihydroxy metabolites that have no affinity for 5-HT _2c receptors and low affinity (about 3-4 orders of magnitude) for MT receptors, thus failing.

The absolute bioavailability of agomelatine is less than 5%, and some documents even indicate that the measured value is only 1% (for example, Australian Public Assessment Report for Agomelatine, Submission No: PM-2009-00483-3-1).

Because the oral bioavailability of the drug is too poor, it is bound to increase the dosage in clinical application. Poor oral bioavailability can also lead to significant inter-individual variability. Agomelatine has adverse effects on liver enzymes, and more than 1% of drug users will experience elevated ALT/AST (more than three times the upper limit of normal). This adverse reaction is idiosyncratic and dose-related. Therefore, it is particularly important to reduce the oral dose and reduce liver damage by increasing the oral bioavailability of these compounds.

Therefore, there is still a need to develop a novel drug.

The present inventor obtained the compound represented by formula I after intensive research and creative work. The inventors have surprisingly found that the compound of formula I or its pharmaceutically acceptable salt, solvate or their mixture has the following good drug-making properties: Compared with agomelatine, it has the following good properties in receptor binding experiment (MT ₁ , MT ₂ and 5-HT _2c ) show equivalent or higher receptor affinity; show stronger metabolic stability in in vitro and in vivo pharmacokinetic experiments; show stronger metabolic stability in overall animal experiments Pharmacodynamic activity, while showing better safety in acute toxicity experiments.

The research results show that the compound of formula I or its pharmaceutically acceptable salt, solvate, or their mixture can be used for the prevention/treatment of melatoninergic system diseases, tension, anxiety, seasonal affective disorder, cardiovascular Diseases, digestive disorders, schizophrenia, phobias, depression, major depression; sleep disorders, sleep disorders, insomnia or fatigue caused by jet lag; diseases or conditions such as weight disorders.

A first aspect of the disclosure concerns the following:

其中： X為H或者鹵素； R₁ 為CH₃ 或者CD₃ ； R₂ 為CH₃ 、CD₃ 或者C₂ H₅ ； 條件是當X為H時，R₂ 為C₂ H₅ 。1. The compound of formula I or its pharmaceutically acceptable salt, solvate, or their mixture,

Wherein: X is H or halogen; R ₁ is CH ₃ or CD ₃ ; R ₂ is CH ₃ , CD ₃ or C ₂ H ₅ ; the condition is that when X is H, R ₂ is C ₂ H ₅ .

2. The compound of embodiment 1, wherein R ₂ is CH ₃ or C ₂ H ₅ .

3. The compound of embodiment 1 or 2, wherein said X is fluorine or chlorine.

4. The compound according to any one of embodiments 1-3, wherein said R ₁ is CD ₃ .

5. The compound of any one of embodiments _1-4 , wherein said X is fluoro or chloro, and said R1 is _CD3 .

6. The compound of any one of embodiments 1-5, selected from the group consisting of: N-(2-(6-chloro-7-deuteromethoxy-naphthalen-1-yl)ethyl)acetamide; N -(2-(6-Chloro-7-methoxy-naphthalene-1-yl)ethyl)acetamide; N-(2-(6-fluoro-7-deuteromethoxy-naphthalene-1- Base) ethyl) acetamide; N-(2-(6-fluoro-7-methoxy-naphthalen-1-yl) ethyl) acetamide; N-(2-(6-chloro-7- Deuteromethoxy-naphthalen-1-yl)ethyl)propionamide; N-(2-(6-chloro-7-methoxy-naphthalen-1-yl)ethyl)propionamide; N- (2-(6-fluoro-7-methoxy-naphthalen-1-yl)ethyl)propionamide; N-(2-(6-chloro-7-deuteromethoxy-naphthalen-1-yl) ) ethyl) acetamide hydrogen chloride hydrate; N-(2-(6-chloro-7-deuteromethoxy-naphthalene-1-yl) ethyl) acetamide hydrogen chloride; N-(2- (6-Chloro-7-methoxy-naphthalen-1-yl)ethyl)acetamide hydrochloride hydrate; N-(2-(6-chloro-7-methoxy-naphthalen-1-yl) Ethyl)acetamide hydrogen chloride; N-(2-(6-chloro-7-methoxy-naphthalen-1-yl)ethyl)acetamide hydrogen bromide hydrate; N-(2-( 6-chloro-7-methoxy-naphthalen-1-yl)ethyl)acetamide sulfate; N-(2-(6-chloro-7-methoxy-naphthalen-1-yl)ethyl) acetamide methanesulfonate; and N-(2-(6-fluoro-7-methoxy-naphthalen-1-yl)ethyl)acetamide hydrochloride hydrate.

7. A pharmaceutical composition comprising: a therapeutically and/or preventively effective amount of a compound of formula I according to any one of embodiments 1-6 or a pharmaceutically acceptable salt, solvate or their mixture, and pharmaceutically acceptable excipients.

8. A pharmaceutical combination comprising: a) one or more first active ingredients selected from a compound of formula I according to any one of embodiments 1-6, or a pharmaceutically acceptable salt, solvate or A mixture thereof, and b) one or more other active ingredients selected from the group consisting of melatonin receptor agonists and 5-HT _2C receptor antagonists.

9. Use of the compound of formula I according to any one of embodiments 1-6 or a pharmaceutically acceptable salt, solvate or mixture thereof in the preparation of a melatonin receptor agonist.

10. Use of the compound of formula I according to any one of embodiments 1-6 or a pharmaceutically acceptable salt, solvate or mixture thereof in the preparation of a 5-HT _2C receptor antagonist.

11. according to the compound of formula I described in any one of embodiment 1-6 or its pharmaceutically acceptable salt, solvate or their mixture in the preparation prevention or treatment is selected from the medicine of following disease or disease USES IN: Melatoninergic Disorders, Nervousness, Anxiety, Seasonal Affective Disorder, Cardiovascular Disease, Digestive Disorders, Schizophrenia, Phobias, Depression, Major Depression; Sleep Disorders, Sleep Disorders, Aviation Insomnia or fatigue due to jet lag; weight imbalance.

12. a method for the compound of formula I of synthetic embodiment 1, it comprises: Make methoxybenzene or the methoxybenzene of halogen ortho-position substitution and succinic anhydride take place Friedel-Crafts reaction under catalyst action to obtain aromatic ketone, i.e. intermediate Body 1; The ketone carbonyl in Intermediate 1 is reduced to methylene with triethylsilane to obtain Intermediate 2; Intermediate 2 is cyclized under the action of an acid catalyst to obtain tetralin, which is Intermediate 3; Intermediate 3 and cyano The cyanation reaction of acetic acid occurs to obtain dihydronaphthyl acetonitrile, which is intermediate 4; the dehydrogenation of intermediate 4 obtains naphthyl acetonitrile, which is intermediate 5; and intermediate 5 reacts with sodium borohydride and acetonitrile in the presence of catalyst nickel chloride hexahydrate Acid anhydride or propionic anhydride react to give acetamide or propionamide compound.

13. The method of embodiment 12, which also includes: dissolving the acetamide or acrylamide compound in toluene and reacting with anhydrous aluminum chloride to obtain naphthol; and reacting the naphthol with deuterated methyl iodide A deuterated acetamide or acylamide compound is obtained.

14. The method of embodiment 12 or 13, further comprising: reacting an acetamide or acrylamide compound or a deuterated acetamide or acrylamide compound with an acid to form a salt.

15. A compound of formula I according to any one of embodiments 1-6, or a pharmaceutically acceptable salt, solvate or mixture thereof, for use as a medicament.

16. The compound of formula I according to any one of embodiments 1-6, or a pharmaceutically acceptable salt, solvate or mixture thereof, for use in the prevention or treatment of a disease or condition selected from the group consisting of: Disorders of the melatoninergic system, stress, anxiety, seasonal affective disorder, cardiovascular disease, digestive disease, schizophrenia, phobias, depression, major depressive disorder; sleep disturbance, sleep disturbance, insomnia due to jet lag or fatigue; weight loss.

17. A kind of prevention or treatment selected from melatoninergic system disease, tension, anxiety disorder, seasonal affective disorder, cardiovascular disease, digestive system disease, schizophrenia, phobia, depression, major depressive disorder; sleep disorder, Sleep disorders, insomnia or fatigue due to jet lag; a method for a disease or condition of a weight disorder comprising administering to a subject in need thereof a compound of formula I according to any one of embodiments 1-6 Compounds or pharmaceutically acceptable salts, solvates or mixtures thereof.

18. A kind of prevention or treatment selected from melatoninergic system disease, tension, anxiety disorder, seasonal affective disorder, cardiovascular disease, digestive system disease, schizophrenia, phobia, depression, major depressive disorder; sleep disorder, A sleep disorder, insomnia or fatigue due to jet lag; a method for a disease or condition of a weight disorder comprising administering a pharmaceutical composition according to embodiment 7 to a subject in need thereof.

19. A method for preventing or treating diseases selected from melatoninergic system diseases, tension, anxiety, seasonal affective disorder, cardiovascular disease, digestive system disease, schizophrenia, phobia, depression, major depressive disorder; sleep disorder, A sleep disorder, insomnia or fatigue caused by jet lag; a method for a disease or condition of a weight disorder comprising administering simultaneously or sequentially a pharmaceutical combination according to embodiment 8 to a subject in need thereof.

20. A drug selected from the group consisting of melatoninergic system diseases, tension, anxiety, seasonal affective disorder, cardiovascular disease, digestive system disease, schizophrenia, phobia, depression, major depressive disorder; sleep Disorder, sleep disorder, insomnia or fatigue caused by jet lag; a pharmaceutical composition for a disease or condition of weight disorder comprising a compound of formula I according to any one of embodiments 1-6 or a pharmaceutically acceptable salts, solvates or mixtures thereof.

The second aspect of the present disclosure relates to the use of the compound described in any one of the above embodiments or a pharmaceutically acceptable salt, solvate or mixture thereof for preventing or treating a disease or condition.

The third aspect of the present disclosure relates to the compound described in any one of the above embodiments or a pharmaceutically acceptable salt, solvate or mixture thereof for the prevention or treatment of a subject selected from Use in the following diseases or conditions: melatoninergic system disorders, nervousness, anxiety, seasonal affective disorder, cardiovascular disease, digestive system disease, schizophrenia, phobias, depression, major depressive disorder; sleep sleep disorders, insomnia or fatigue due to jet lag; weight disorders.

The fourth aspect of the present disclosure relates to a method for preparing the compound described in any one of the above embodiments or a pharmaceutically acceptable salt, solvate or mixture thereof.

definition

The term "metabolic stability" in this application refers to the ability of a compound to enter and exist stably in the body in the form of the original drug without being metabolized into other structural forms.

The term "pharmaceutically acceptable" in this application refers to: a compound or composition is chemically and/or toxicologically compatible with other ingredients constituting the preparation and/or with human beings using it to prevent or treat a disease or condition or mammal compatible.

The term "subject" or "patient" in this application includes humans and mammals.

The term "adjuvant" in this application refers to an excipient or vehicle used to administer a compound, including but not limited to diluents, disintegrants, precipitation inhibitors, surfactants, glidants, binders Agents, lubricants, coating materials, etc. Excipients are generally described in "Remington's Pharmaceutical Sciences" by E.W. Martin. Examples of excipients include, but are not limited to, aluminum monostearate, aluminum stearate, carboxymethylcellulose, sodium carboxymethylcellulose, crospovidone, glyceryl isostearate, glyceryl monostearate, Hydroxyethyl Cellulose, Hydroxy Methyl Cellulose, Hydroxy Octacyl Hydroxystearate, Hydroxy Propyl Cellulose, Hydroxy Propyl Methyl Cellulose, Lactose, Lactose Monohydrate, Magnesium Stearate, Mannitol , microcrystalline cellulose, etc.

In the context of this application, unless specifically stated to the contrary, the term "treatment" may also include prophylaxis.

The term "solvate" in this application refers to a complex formed by combining a compound of formula I or a pharmaceutically acceptable salt thereof with a solvent. It is to be understood that any solvates of the compounds of Formula I used in the treatment of the diseases or conditions described herein, while possibly providing different properties, including pharmacokinetic properties, once absorbed into a subject, Compounds of formula I will be obtained such that the use of compounds of formula I respectively encompasses the use of any solvates of compounds of formula I.

The term "hydrate" refers to the case where the solvent in the above term "solvate" is water.

It is further understood that compounds of formula I, or pharmaceutically acceptable salts thereof, may be isolated in the form of solvates, and therefore any such solvates are included within the scope of the present invention. For example, a compound of formula I, or a pharmaceutically acceptable salt thereof, can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.

The term "pharmaceutically acceptable salt" refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present disclosure. See, eg, SM Berge et al. "Pharmaceutical Salts", J. Pharm. Sci. 1977, 66, 1-19. Among them, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid or nitric acid, etc.; organic acids such as formic acid, acetic acid, acetylacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, Acid, Undecanoic Acid, Lauric Acid, Benzoic Acid, Salicylic Acid, 2-(4-Hydroxybenzoyl)-benzoic Acid, Camphoric Acid, Cinnamic Acid, Cyclopentanepropionic Acid, Digluconic Acid, 3-Hydroxy -2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoro Methanesulfonic acid, laurylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalene disulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid Acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptonic acid, glycerol phosphate, day Aspartic acid, sulfosalicylic acid, etc. For example, HCl (or hydrochloric acid), HBr (or hydrobromic acid solution), methanesulfonic acid, sulfuric acid, tartaric acid or fumaric acid can be used to form a pharmaceutically acceptable salt with the compound represented by formula I.

It should be understood that the term "compound of the present disclosure" used in the application can include according to the context: the amide compound shown in formula I, its pharmaceutically acceptable salt, its solvate, and the solvent of its pharmaceutically acceptable salt compounds, and their mixtures.

其中： X為H或者鹵素； R₁ 為CH₃ 或者CD₃ ； R₂ 為CH₃ 或者C₂ H₅ ； 條件是當X為H時，R₂ 不為CH₃ 。At least one embodiment of the present disclosure provides a compound represented by formula I or a pharmaceutically acceptable salt, solvate or mixture thereof,

Wherein: X is H or halogen; R ₁ is CH ₃ or CD ₃ ; R ₂ is CH ₃ or C ₂ H ₅ ; the condition is that when X is H, R ₂ is not CH ₃ .

Compounds excluded from the structural scope of formula I: agomelatine (X is H, R ₁ and R ₂ are both CH ₃ ) and d3 -agomelatine (X is H, R ₁ is CD ₃ , R ₂ is _CH3 ).

In one embodiment, X is F, Cl, Br or I; eg, F or Cl.

In _one embodiment, R1 is _CH3 .

In _one embodiment, R1 is _CD3 .

In one embodiment, X is F, Cl, Br or _I , and R1 is _CD3 .

In _one embodiment, X is F, Cl or Br, and R1 is _CD3 .

In _one embodiment, X is F or Cl, and R1 is _CD3 .

In one embodiment, X is Cl and R ₁ is CD ₃ .

In _one embodiment, X is _Cl , and R1 is _CD3 , R2 is _CH3 .

The pharmaceutical complex provided by at least one embodiment of the present disclosure may include the complex form formed by the compound of formula I and HCl, HBr, methanesulfonic acid, sulfuric acid, tartaric acid, fumaric acid, and also include its corresponding solvate ( such as hydrates).

In an exemplary embodiment, the compound is selected from the compounds or salts/hydrates thereof in Table 1 below: Table 1: Example Compounds

In this application, when the name of the compound is inconsistent with the structural formula, the structural formula shall prevail.

At least one embodiment of the present disclosure provides a medicament that is a melatonin receptor agonist, comprising a compound of the present disclosure as an active ingredient.

At least one embodiment of the present disclosure provides a medicament that is a 5-HT _2C receptor antagonist comprising a compound of the present disclosure as an active ingredient.

At least one embodiment of the present disclosure provides a medicament that acts as both a melatonin receptor agonist and a 5-HT _2C receptor antagonist, comprising a compound of the present disclosure as an active ingredient.

The disclosed compound can be used to prevent or treat melatoninergic system diseases, tension, anxiety, seasonal affective disorder, cardiovascular disease, digestive system disease, schizophrenia, phobia in subjects (including humans and mammals) , depression, major depressive disorder; sleep disorders, sleep disturbances, insomnia or fatigue due to jet lag; weight disorders. For example, the compound described in any one of the above-mentioned embodiments of the present disclosure or a pharmaceutically acceptable salt, solvate or mixture thereof is used for preventing or treating a disease selected from the following in a subject in need thereof or use in a medical condition: depression, anxiety, sleep disorders, weight disorders.

At least one embodiment of the present disclosure provides a method of producing a pharmaceutical composition comprising mixing at least one compound according to any of the compound embodiments disclosed herein with a pharmaceutical excipient.

The disclosed compounds can be formulated into pharmaceutical preparations, including dosage forms suitable for oral administration (for example, as tablets, pills, syrups, powders, granules, or capsules), for parenteral injection (for example, intravenous, subcutaneous injection), formulations suitable for topical administration (eg, as an ointment, patch or cream), and formulations suitable for rectal administration (eg, as a suppository).

Depending on the disease and patient to be treated and the route of administration, the pharmaceutical preparations of the present disclosure can be administered once or several times a day in different doses. For example, a daily dosage of a compound of the present disclosure may be about 0.1-0.4 mg/kg body weight orally administered.

In certain aspects, the disclosed compounds may be administered alone, or in combination with other compounds, including other melatonin receptor agonists or other 5- _HT2C receptor antagonists or other therapeutic agents. For example, the compound of the present disclosure can be administered in combination with one or more drugs selected from melatonin, agomelatine, zemiladine, and tasimelatine. The term "pharmaceutical combination" or "administration in combination" as used herein may encompass situations of simultaneous or sequential administration.

At least one embodiment of the present disclosure provides a method for preparing the above-mentioned compound of the present disclosure or a pharmaceutically acceptable salt, solvate or mixture thereof.

Exemplary reaction scheme (taking embodiment 1,2,8 as example):

At least one embodiment of the present disclosure provides a method for synthesizing a compound of formula I, which includes: making methoxybenzene or methoxybenzene substituted by halogen ortho-position and succinic anhydride undergo Friedel-Kuaff reaction under the action of a catalyst Special (Friedel-Crafts) reaction to obtain aromatic ketones, namely intermediate 1; the ketone carbonyl in intermediate 1 is reduced to methylene with triethylsilane to obtain intermediate 2; intermediate 2 is cyclized under the action of an acidic catalyst to obtain tetrahydrogenation Naphthalene is intermediate 3; intermediate 3 is cyanided with cyanoacetic acid to obtain dihydronaphthyl acetonitrile, which is intermediate 4; intermediate 4 is dehydrogenated to obtain naphthyl acetonitrile, which is intermediate 5; and intermediate 5 is hydrated in the catalyst hexahydrate React with sodium borohydride and acetic anhydride/propionic anhydride in the presence of nickel chloride to obtain acetamide/acrylamide compound.

In at least one embodiment of the present disclosure, the synthesis method may further include: dissolving the above-mentioned acetamide/acrylamide compound in toluene and reacting with anhydrous aluminum chloride to obtain naphthol; and making the naphthol react with deuterium The reaction of iodomethane gives the deuterated acetamide/propionamide compound.

In at least one embodiment of the present disclosure, the synthesis method may further include: reacting the above-mentioned acetamide/acrylamide compound or deuterated acetamide/acrylamide compound with an acid to form a salt.

For specific operations, for example, reference may be made to the description of the embodiments.

According to the detailed teaching of the present disclosure and the existing synthetic general knowledge, those skilled in the art can easily synthesize the compound of formula I disclosed in the present disclosure.

At least one embodiment of the present disclosure provides a pharmaceutical composition comprising a therapeutically and/or preventively effective amount of any one of the compounds described in the present disclosure or a pharmaceutically acceptable salt, solvate or mixture thereof, and Optional pharmaceutically acceptable excipients.

At least one embodiment of the present disclosure provides prevention or treatment of melatoninergic system disorders, stress, anxiety, seasonal affective disorder, cardiovascular disease, digestive system disease, schizophrenia, phobias, depression, major depressive disorder; A method for a sleep disorder, sleep disorder, insomnia or fatigue caused by jet lag; weight disorder, etc., comprising administering a pharmaceutical composition of the present disclosure to a subject in need thereof .

At least one embodiment of the present disclosure provides the compounds described in the present disclosure or pharmaceutically acceptable salts, solvates or mixtures thereof for the treatment of melatoninergic system diseases, stress, anxiety, seasonal affective disorder, Cardiovascular diseases, digestive system diseases, schizophrenia, phobias, depression, major depression; sleep disorders, sleep disorders, insomnia or fatigue caused by jet lag; weight disorders and other diseases or conditions.

In the context of this disclosure, the following abbreviations are used: TLC: thin layer chromatography DDQ: 2,3-dichloro-5,6-dicyano-1,4-benzoquinone TFA: trifluoroacetic acid DMSO: dimethyl Asia

The embodiments of the present disclosure will be described in detail below in conjunction with examples, but those skilled in the art will understand that the following examples are only for illustrating the present invention, and should not be regarded as limiting the scope of the present invention.

Those who do not indicate the specific conditions in the examples are carried out according to the conventional conditions or the conditions suggested by the manufacturer. The reagents or instruments used were not indicated by the manufacturer, and they were all commercially available conventional products.

The first part: the synthesis of embodiment compound

Synthesis of Example 1 and Examples 2 and 8 : The reaction scheme is as above, and the specific synthesis operation is as follows: Intermediate 1 : 3 liters of three-necked flask, with a condenser on the shelf. Add 328 grams (2.46 mol) of aluminum trichloride into 1.7 liters of dichloromethane under an ice bath, and stir to dissolve it completely. Add 156.8 g (138 mL, 1.10 mol) of o-chloroanisole at one time, and then add 123 g (1.23 mol) of succinic anhydride in batches, the system will generate heat and gas, and spontaneous reflux will occur. After the spontaneous reflux is over, start heating to reflux. After refluxing for 2 hours, the progress of the reaction was monitored by TLC, and the reaction was terminated when the starting material disappeared. After natural cooling, pour into 5 liters of ice water. Under stirring, it was acidified with 300 ml of concentrated hydrochloric acid, and a large amount of solids appeared in the system. After stirring for half an hour, it was filtered, and the filter cake was washed with 1 liter of water, and then recrystallized with ethanol/water to obtain a white or light pink powder. Yield: 79.2%, melting point 186-188°C. NMR: ¹ H-NMR(400MHz, DMSO- d6 ), δ:2.54-2.57(t, 2H, J=6.16Hz), 3.19-3.23(t, 2H, J=6.20Hz), 3.95(s, 3H) , 7.27-7.29(d, 1H, J=9.24Hz), 7.97-8.00(m, 2H), 12.16(s, 1H).

Intermediate 2 : Add 121.4 g (0.5 mol) of Intermediate 1 into a 1-liter eggplant-shaped flask, then add 270 ml of trifluoroacetic acid and 180 ml of triethylsilane, and stir to reflux. After refluxing for 5 hours, the progress of the reaction was monitored by TLC, and the reaction was terminated when the raw material disappeared. Rotary evaporate until the system has no obvious solvent distillation, add 1 liter of ethyl acetate, wash with 500 ml of water x 3 times, and then wash with 3 mol/L NaOH aqueous solution 300 ml x 2 times. The aqueous NaOH phases were combined and acidified with 6 mol/L hydrochloric acid in an ice bath to obtain a large amount of white precipitate. Filter and dry the filter cake to obtain the crude product, yield: 94.6%. The crude product can be put directly into the next step, or recrystallized from ethyl acetate/cyclohexane to obtain colorless crystals, melting point: 63-66°C. NMR: ¹ H-NMR(400MHz, DMSO -d6 ), δ:1.73-1.79(m, 2H), 2.16-2.20(t, 2H, J=7.28Hz), 2.51-2.54(m, 2H), 3.81( s, 3H), 7.04-7.06(d, 1H, J=8.44Hz), 7.10-7.13(dd, 1H, J ₁ =8.40Hz, J ₂ =1.88Hz), 7.24-7.25(d, 1H, J= 1.96Hz), 12.15(s, 1H).

Intermediate 3 : 113 grams of Intermediate 2 , 480 milliliters of trifluoroacetic acid and 120 milliliters of methanesulfonic acid were added, the mixture was heated and refluxed for 7 hours, and the progress of the reaction was monitored by TLC. The reaction was terminated when the raw materials disappeared. After cooling, it was poured into 2.5 liters of ice water and stirred, and a large amount of light yellow solid appeared, which was filtered and washed with water. The filter cake was recrystallized with ethanol/water to obtain light yellow crystals with a yield of 75.6%. Melting point: 105-108℃ NMR: ¹ H-NMR(400MHz, CDCl ₃ ), δ:2.09-2.16(m, 2H), 2.62-2.65(t, 2H, J=6.8Hz), 2.87-2.90(t, 2H, J=6.2Hz), 3.94(s, 3H), 7.28(s, 1H), 7.56(s, 1H).

Intermediate 4 : Add 75.0 grams of Intermediate 3 , 45.6 grams of cyanoacetic acid, 10 grams of benzylamine, 12 grams of heptanoic acid, and 700 milliliters of toluene into a 1-liter three-necked flask, add a water separator, and reflux at an external temperature of 140 ° C. water. After 24 hours, TLC monitored the end of the reaction. After cooling, wash with water twice, filter out insoluble matter, spin dry the solvent and recrystallize with ethanol/water to obtain pale yellow crystals. Yield 88.3%, melting point: 100-104°C. NMR: ¹ H-NMR(400MHz, DMSO -d6 ), δ:2.31-2.36(m, 2H), 2.69-2.73(t, 2H, J=8.26Hz), 3.49(s, 2H), 3.92(s, 3H), 6.26-6.28(t, 1H, J=4.34Hz), 6.69(s, 1H), 7.18(s, 1H).

Intermediate 5 : 70.1 g of Intermediate 4 was dissolved in 900 ml of dichloromethane, 75 g (0.33 mol) of DDQ was added in batches under external cooling, and the internal temperature was controlled not to exceed 20°C. After the addition, the system turned black, and the temperature was kept at 20°C for 30 minutes, and the reaction was monitored by TLC. The solid was removed by filtration, and the filtrate was washed twice with 400 ml of saturated aqueous sodium carbonate solution until it was colorless, and then washed once with 300 ml of saturated brine. The organic phase was dried with anhydrous sodium sulfate, filtered and spin-dried to dry the solvent, and then recrystallized with cyclohexane/ethyl acetate to obtain white crystals. Yield: 90.7%, melting point: 140-144℃ NMR: ¹ H-NMR (400MHz, CDCl3), δ: 4.05(s, 2H), 4.08(s, 3H), 7.12(s, 1H), 7.35-7.39( dd, 1H, J ₁ =8.14, J ₂ =7.28), 7.54-7.56(d, 1H, J=7.24), 7.72-7.74(d, 1H, J=8.12), 7.93(s, 1H).

Intermediate 6 ( i.e. Example 2) : N-(2-(6-chloro-7-methoxy-naphthalene-1-yl) ethyl) acetamide 36.0 g intermediate 5 , dissolved in 700 ml of anhydrous methanol And in the mixed solution of 1300 milliliters of dichloromethane, under the cooling of -10 ℃, add 23 grams of nickel chloride hexahydrate thereinto, make it dissolve completely under stirring. Add 35 milliliters of acetic anhydride thereto, and then add 26.4 grams of sodium borohydride in batches, and control the adding speed so that the internal temperature is between 0-10°C. After the addition, move to room temperature and stir for 3 hours. TLC monitors that the reaction is complete. Under cooling in an ice bath, 500 ml of 3 mol/L hydrochloric acid is added thereto, and stirred for 1 hour. The organic solvent was removed by rotary evaporation, and 1 liter of ethyl acetate was added to the residue, followed by washing with 500 ml of water, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was added with 4.3 g of activated carbon and boiled for 30 minutes, then filtered, the filtrate was spin-dried, and treated with cyclohexane/ethyl acetate to obtain a white solid. Yield 72.1%, melting point: 142-145°C. NMR: ¹ H-NMR(400MHz, DMSO -d6 ), δ: 1.83(s, 3H), 3.11-3.15(m, 2H), 3.30-3.34(m, 2H), 4.05(s, 3H); 7.30- 7.36(m, 2H); 7.70-7.72(d, 1H, J=7.60Hz); 7.79(s, 1H); 8.07 (s, 1H); 8.14-8.17(t, 1H, J=5.60Hz). - MS m/e: 278.1 ([M+1] ⁺ ).

Intermediate 7 : 23.5 grams of Intermediate 6 were dissolved in 1000 milliliters of toluene, 25.2 grams of anhydrous aluminum trichloride was added, the reaction was monitored by TLC after reflux for 1.5 hours, the toluene was poured after cooling, and 600 milliliters of ethyl acetate was added to the residue , and then successively washed with 300 ml of saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, the organic phase was dried with anhydrous sodium sulfate, filtered, and spin-dried to dry the solvent, and then treated with cyclohexane/ethyl acetate to obtain a light yellow solid. Yield: 82.0%, melting point: 174-176°C. ¹ H-NMR(400MHz, DMSO -d6 ), δ:1.80(s, 3H), 3.10-3.14(t, 2H, J=7.28Hz), 3.33-3.38(m, 2H), 7.23-7.28(m, 2H), 7.49(s, 1H), 7.65-7.68(dd, 1H, J ₁ =7.32Hz, J ₂ =2.28Hz), 7.98-8.02(m, 2H), 10.52(s,1H).

Embodiment 1 : N-(2-(6-chloro-7-deuteromethoxy-naphthalene-1-yl) ethyl) acetamide 17.3 grams of intermediate 7 are dissolved in 1 liter of acetone, to which 27.2 gram of salt of wormwood, 1.3 gram of potassium iodide, 12.4 gram (5.31 milliliters) deuterated methyl iodide, TLC monitoring reaction is complete after room temperature reaction 24 hours, filters, and the filtrate is spin-dried, adds 400 milliliters of ethyl acetates in the residue, then successively with Wash with 200 ml of water and saturated aqueous sodium chloride solution, dry the organic phase with anhydrous sodium sulfate, and filter, add 2 g of activated carbon to the filtrate and boil for 30 minutes, then filter, spin dry, and treat with cyclohexane/ethyl acetate to obtain a white powder shaped solid. Yield 81.4%, melting point: 148-151℃ ¹ H-NMR (400MHz, DMSO -d6 ), δ: 1.83(s, 3H), 3.11-3.20(m, 2H), 3.29-3.35(m, 2H), 7.30-7.36(m, 2H), 7.70-7.72(dd, 1H, J ₁ =7.80Hz, J ₂ =1.40Hz), 7.80(s, 1H), 8.07(s, 1H), 8.15-8.18(t, 1H, J=5.46Hz). ESI-MS m/e: 281.1 ([M+1] ⁺ ).

Example 8 : under ice bath, 1.0 g of Example 1 was dissolved in 30 ml of ethyl acetate, 0.50 ml of concentrated hydrochloric acid was added thereto, a large amount of white solid was precipitated after stirring for 1 hour, filtered, washed with 10 ml of cold ethyl acetate, After drying, 0.89 g of white solid was obtained with a yield of 78.8%. Melting point: 102-105°C. ¹ H-NMR(400MHz, DMSO -d6 ),. δ: 1.83(s, 3H), 3.11-3.20(m, 2H), 3.29-3.35(m, 2H), 7.30-7.36(m, 2H), 7.70 -7.72(dd, 1H, J ₁ =7.80Hz, J ₂ =1.40Hz), 7.80(s, 1H), 8.07(s, 1H), 8.15-8.18(t, 1H, J=5.46Hz). (hydrogen The spectrum data is actually the same as in Example 1, only the water peak position and area are different).

The synthesis of Examples 3 and 4 is the same as the synthesis of Examples 1 and 2 , except that the starting material is replaced by o-fluoroanisole.

白色固體，熔點：141-144℃。¹ H-NMR(400MHz, DMSO-d6 ), δ: 1.83(s, 3H), 3.10-3.14(m, 2Hz), 3.29-3.35(m, 4H), 7.31-7.32(m, 2H), 7.68-7.71(m, 1H), 7.72-7.75(d, 1H, J=12.32Hz), 7.82-7.85(d, 1H, J=8.96Hz), 8.15-8.18(t, 1H, J=5.62Hz). ESI-MS m/e：265.1([M+1]⁺ )。 Example 3

White solid, melting point: 141-144°C. ¹ H-NMR(400MHz, DMSO -d6 ), δ: 1.83(s, 3H), 3.10-3.14(m, 2Hz), 3.29-3.35(m, 4H), 7.31-7.32(m, 2H), 7.68- 7.71(m, 1H), 7.72-7.75(d, 1H, J=12.32Hz), 7.82-7.85(d, 1H, J=8.96Hz), 8.15-8.18(t, 1H, J=5.62Hz). ESI - MS m/e: 265.1 ([M+1] ⁺ ).

白色固體，熔點140-144℃。¹ H-NMR(400MHz, DMSO-d6 ), δ: 1.83(s, 3H), 3.11-3.15(m, 2Hz), 3.29-3.36(m, 4H), 4.05(s, 3H), 7.30-7.32(m, 2H), 7.69-7.72(m, 1H), 7.73-7.76(d, 1H, J=12.44Hz), 7.82-7.85(d, 1H, J=8.98Hz), 8.16-8.19(t, 1H, J=5.54Hz). ESI-MS m/e：262.1([M+1]⁺ )。 Embodiment 4 : N-(2-(6- fluoro -7- methoxy- naphthalen - 1 -yl ) ethyl ) acetamide

White solid, melting point 140-144°C. ¹ H-NMR(400MHz, DMSO -d6 ), δ: 1.83(s, 3H), 3.11-3.15(m, 2Hz), 3.29-3.36(m, 4H), 4.05(s, 3H), 7.30-7.32( m, 2H), 7.69-7.72(m, 1H), 7.73-7.76(d, 1H, J=12.44Hz), 7.82-7.85(d, 1H, J=8.98Hz), 8.16-8.19(t, 1H, J=5.54Hz). ESI-MS m/e: 262.1 ([M+1] ⁺ ).

The synthesis of Examples 5 and 6 is the same as the synthesis of Examples 1 and 2 , except that acetic anhydride is replaced by propionic anhydride in the sixth step of synthesis.

白色固體。¹ H-NMR(400MHz, DMSO-d6 )，δ: 1.00-1.03(t, 3H, J=7.56Hz), 2.07-2.12(q, 2H, J=7.56Hz), 3.12-3.17(m, 2H), 3.32-3.38(m, 2H), 7.32-7.38(m, 2H), 7.72-7.74(dd, 1H, J₁ =6.88Hz, J₂ =1.92Hz), 7.77(s, 1H), 8.01-8.03(t, 1H, J=5.60Hz), 8.07(s, 1H). ESI-MS m/e：295.1([M+1]⁺ )。 Embodiment 5 : N-(2-(6- chloro -7- deuteromethoxy- naphthalene - 1 -yl ) ethyl ) propionamide

white solid. ¹ H-NMR(400MHz, DMSO -d6 ), δ: 1.00-1.03(t, 3H, J=7.56Hz), 2.07-2.12(q, 2H, J=7.56Hz), 3.12-3.17(m, 2H) , 3.32-3.38(m, 2H), 7.32-7.38(m, 2H), 7.72-7.74(dd, 1H, J ₁ =6.88Hz, J ₂ =1.92Hz), 7.77(s, 1H), 8.01-8.03 (t, 1H, J=5.60Hz), 8.07(s, 1H). ESI-MS m/e: 295.1 ([M+1] ⁺ ).

白色固體。¹ H-NMR(400MHz, DMSO-d6 ), δ: 0.99-1.02(t, 3H, J=7.60Hz), 2.06-2.11(q, 2H, J=7.60Hz), 3.12-3.16(m, 2H), 3.31-3.37(m, 2H), 4.05(s, 3H), 7.30-7.36(m, 2H), 7.70-7.72(dd, 1H, J₁ =7.12Hz, J₂ =1.96Hz), 7.76(s, 1H), 8.00-8.02(t, 1H, J=5.50Hz), 8.06(s, 1H). ESI-MS m/e：292.1([M+1]⁺ )。 Embodiment 6 : N-(2-(6- chloro -7- methoxy- naphthalen - 1 -yl ) ethyl ) propionamide

white solid. ¹ H-NMR(400MHz, DMSO -d6 ), δ: 0.99-1.02(t, 3H, J=7.60Hz), 2.06-2.11(q, 2H, J=7.60Hz), 3.12-3.16(m, 2H) , 3.31-3.37(m, 2H), 4.05(s, 3H), 7.30-7.36(m, 2H), 7.70-7.72(dd, 1H, J ₁ =7.12Hz, J ₂ =1.96Hz), 7.76(s , 1H), 8.00-8.02(t, 1H, J=5.50Hz), 8.06(s, 1H). ESI-MS m/e: 292.1([M+1] ⁺ ).

合成同實施例4 ，只是在第六步合成時將乙酸酐替換為丙酸酐。白色固體，¹ H-NMR(400MHz, DMSO-d6 ), δ: 0.98-1.01(t, 3H, J=7.52Hz), 2.05-2.10(q, 2H, J=7.52Hz), 3.10-3.14(m, 2Hz), 3.28-3.35(m, 4H), 4.04(s, 3H), 7.30-7.32(m, 2H), 7.68-7.71(m, 1H), 7.73-7.76(d, 1H, J=12.52Hz), 7.81-7.84(d, 1H, J=9.02Hz), 8.02-8.04(t, 1H, J=5.58Hz). ESI-MS m/e：276.1([M+1]⁺ )。 Example 7 : N-(2-(6- fluoro -7- methoxy- naphthalen - 1 -yl ) ethyl ) acrylamide

Synthesis is the same as in Example 4 , except that acetic anhydride is replaced by propionic anhydride during the synthesis of the sixth step. White solid, ¹ H-NMR(400MHz, DMSO -d6 ), δ: 0.98-1.01(t, 3H, J=7.52Hz), 2.05-2.10(q, 2H, J=7.52Hz), 3.10-3.14(m , 2Hz), 3.28-3.35(m, 4H), 4.04(s, 3H), 7.30-7.32(m, 2H), 7.68-7.71(m, 1H), 7.73-7.76(d, 1H, J=12.52Hz ), 7.81-7.84(d, 1H, J=9.02Hz), 8.02-8.04(t, 1H, J=5.58Hz). ESI-MS m/e: 276.1([M+1] ⁺ ).

Synthesis of Examples 9-15 The synthesis of Examples 9-15 is the same as that of Example 8 . 1.0 g of the corresponding example compound was dissolved in 30 ml of ethyl acetate in an ice bath, and then a certain amount of acid was added respectively, and a precipitate was precipitated by stirring, filtered and washed with ethyl acetate to obtain a white solid. If mineral acids (HCl/HBr/H ₂ SO ₄ etc.) are used, the ¹ H-NMR of the new example is exactly the same as that of the original example except that the area and position of the water peak are slightly different. In the following examples, no Repeat again; if there is an organic acid, the ¹ H-NMR of the new example is different from the original example. The specific operation and information are as follows:

Embodiment 9 : 1.0 grams of embodiment 1 , add 2 milliliters of anhydrous HCl/ethyl acetate solution of 3.5 mol/L. Melting point 106-108°C, yield: 77.8%.

Embodiment 10 : 1.0 grams of embodiment 2 , add 0.50 milliliters of concentrated hydrochloric acid. Melting point 100-103°C, yield: 82.3%.

Embodiment 11 : 1.0 grams of embodiment 2 , add 2 milliliters of 3.5 mol/L HCl/ethyl acetate solution. Melting point 104-107°C, yield: 80.5%.

Embodiment 12 : 1.0 grams of embodiment 2 , add 0.61 milliliters of 40% HBr aqueous solution. Melting point 145-151°C, yield: 76.9%.

Embodiment 13 : 1.0 grams of embodiment 2 , add 0.23 milliliters of concentrated sulfuric acid. Melting point 186-190°C, yield: 92.1%.

Example 14 : 1.0 g of Example 2 was added with 0.25 ml of methanesulfonic acid. Melting point 156-159°C, yield: 68.4%. ¹ H-NMR (400MHz, DMSO -d6 ), δ: 1.84(s, 3H), 2.33(s, 3H), 3.13-3.17(m, 2H), 3.31-3.36(m, 2H), 4.06(s, 3H); 7.32-7.38(m, 2H); 7.72-7.74(d, 1H, J=7.28Hz); 7.81(s, 1H); 8.09 (s, 1H); 8.16-8.19(t, 1H, J= 5.44Hz).

Example 15 : 1.0 g of Example 4 was added with 0.50 ml of concentrated hydrochloric acid. The melting point is 104-107°C, and the yield is 76.2%.

Reference substance d3 - synthesis of agomelatine The reference substance is a known compound, which is used as a reference substance for activity evaluation. It is synthesized in the same manner as in Example 1 , except that intermediate 6 is replaced by agomelatine. White solid, melting point: 95-97°C. ¹ H-NMR(400MHz, DMSO -d6 ), δ: 1.83(s, 3H); 3.10-3.14(m, 2H); 3.30-3.35(m, 2H); 7.15-7.18(dd, 1H, J1=8.60 Hz; J2=2.44Hz); 7.24-7.32(m, 2H); 7.61-7.60(d, 1H, J=2.52Hz); 7.70-7.72(d, 1H, J=7.84Hz); 7.81-7.83(d , 1H, J=8.96Hz); 8.11-8.14(t, 1H, J=5.60Hz).

Part II: In vitro receptor binding experiments of the compounds of the examples Taking agomelatine (abbreviated as Ago) and d3 -agomelatine (abbreviated as d3 -Ago) as references, the compounds of the examples were subjected to in vitro receptor binding experiments. Body binding experiments to evaluate the competitive binding ability of test compounds and radioligands to receptors in vitro. Receptors include MT _1/ MT ₂ receptors and 5-HT _2c receptors. The experiment is divided into two parts: primary screening and re-screening. The results of the primary screening are expressed by the binding percentage, and the results of the re-screening are expressed by the IC ₅₀ value (unit M, that is, mol/L).

Experimental materials and reagents (1) Human MT ₁ /MT ₂ receptor membrane proteins are _PerkinElmer products ES-620 (MT ₁ ) and ES-621 (MT ₂ ); The nuclear-cytoplasmic-membrane preparation kit method of Lai Gene Technology Co., Ltd. is extracted from rat hippocampus and stably transfected HEK293 cell line. (2) The labeled ligand used in the test is the product of PE Company, the unlabeled ligand is the product of Sigma Company; phenylmethylsulfonyl fluoride (PMSF) is the product of Sigma Company; the scintillation fluid is the product of PE Company; Folin-phenol reagent is the product of Warwick Products of Keyi Company; other reagents were of analytical grade. (3) Tris-HCl buffer solution ratio: 50mM Tris-HCl buffer solution, 1mM EDTA, 5mM MgCl ₂ , 0.1% NaN ₃ , and then add a certain proportion of PMSF to adjust the pH to 7.4. (4) The compound of the test example was dissolved in DMSO to prepare a 10 ^-2 M stock solution, and then diluted with distilled water to form a concentration gradient of 10 ^-4 -10 ^-11 M. The concentration of 10 ^-5 M was selected for the primary screening of MT receptor binding assay; two concentrations of 10 ^-5 and 10 ^-7 M were selected for the primary screening of 5-HT _2c receptor binding assay.

Data processing and statistical analysis GraphPad Prism 5.0 software was used for statistical analysis. Receptor binding experiment formula: Inhibition rate (%)=[(total binding CPM number-dosing tube CPM)/(total binding CPM-non-specific CPM)]×100%, CPM is radioactive intensity count. The logarithmic concentration of the test compound was fitted nonlinearly with the specific binding percentage to obtain the competition inhibition curve and calculate the IC ₅₀ value.

1. MT 1 / _{MT 2} receptor binding experiment Place the test tubes in the reaction condition of 25°C. 10 μL of receptor membrane protein MT ₁ or MT ₂ was added to all test tubes. Add 50 μL of the corresponding non-labeled ligand Ago with a concentration of 10 ⁻⁴ M to the non-specific binding tube, the final concentration is 10 μM, and react for 30 minutes in advance. Add 30 μL of the test drug (MT ₁ : 10 ^-4 -10 ^-10 M concentration, MT ₂ : 10 ^-4 -10 ^-11 M concentration) to the test tube in sequence; add 40 μL [ ³ H]-melatonin in sequence to all the test tubes . Make up the volume of all reaction tubes to 300μL with Tris-HCl buffer solution (50mM Tris-HCl, 1mM EDTA, 5mM MgCl ₂ , 0.1mM PMSF, 0.1% NaN ₃ , pH7.4); react at 25°C for 1 hour; then spot On type 49 glass fiber filter paper, filter under negative pressure, then wash with ice-cold Tris-HCl buffer solution (50mM Tris-HCl buffer solution, 1mM EDTA, 5mM MgCl ₂ , 0.1% NaN ₃ , pH7.4), 2mL ×3 times, drained. After the filter paper was taken out and dried, put it in a scintillation vial, add 1mL of scintillation liquid, and measure the radioactive intensity with a liquid scintillation counter.

The binding percentage was measured according to the formula, and the IC ₅₀ value was further obtained. The experimental results are shown in Table 2.

Table 2 Results of primary screening (10 ^-5 M) and secondary screening for MT _1/ MT ₂ receptor binding of the compounds of the examples

2. 5 - HT _2c receptor binding experiment Place the test tubes in the reaction condition of 25°C, and add 50 μg receptor membrane protein 5-HT _2c to all the test tubes. Add 50 μL of the corresponding non-labeled ligand 5-HT with a concentration of 10 ⁻⁴ M to the non-specific binding tube, the final concentration is 10 μM, and react for 30 minutes in advance. 30 μL of the compounds of the test examples (10 ^-4 -10 ^-10 M concentration) were sequentially added to the test tube. Add 40 μL [ ³ H]-LSD (lysergic acid diethylamide, lysergic acid diethylamine) to all test tubes sequentially, and add Tris-HCl buffer solution (50 mM Tris-HCl, 1 mM EDTA, 5 mM MgCl ₂ , 0.1% NaN ₃ , 0.1 mM PMSF, pH7.4) to make up the volume of all reaction tubes to 300μL; react at 25°C for 1 hour; then spot on 49-type glass fiber filter paper and filter under negative pressure; then use ice-cold Tris-HCl buffer solution (50mM Tris -HCl buffer solution, 1mM EDTA, 5mM MgCl ₂ , 0.1% NaN ₃ , pH7.4) wash, 2 mL×3 times, and drain. After the filter paper was taken out and dried, it was placed in a scintillation vial, 1 mL of scintillation fluid was added, and the radioactive intensity was measured with a liquid scintillation counter.

The binding percentage was measured according to the formula, and the IC ₅₀ value was further obtained. The experimental results are shown in Table 3.

Table 3 Example compound 5-HT _2c receptor binding screening results

See Figure 1 for the graphical results of in vitro receptor binding experiments of some of the compounds in the examples.

Part III: Metabolism study of the compound of the example The metabolic stability of the compound of the example was judged by in vitro (human liver microsome incubation system) and in vivo (rat oral/tail vein injection model).

Experimental materials and reagents Human liver microsomes (BD Gentest, product number: 452161); acetonitrile, aconitine, and verapamil from Sigma; NADPH (reduced coenzyme II) from Roche; 0.1M pH 7.4 PBS (phosphate Buffer solution, self-prepared); other reagents were of analytical grade.

Male SD rats, weighing 200 ± 20 g, SPF grade, were purchased from Speiford.

Instruments, conditions and parameters TSQ Quantum liquid chromatography-mass spectrometry (LC/MS/MS) from Finnigan Company of the United States, the chromatographic column is TSKgel Amide-80 column (2.0 mm ID×100 mm, 5 μm); the mobile phase is Acetonitrile-water-formic acid (50:50:0.1); flow rate 0.2 mL/min; injection volume 5 μL; column temperature is room temperature. Using electrospray ionization ionization source (ESI), spray voltage 4.8 KV; capillary temperature (TEM) 300 ℃; sheath gas (sheath gas) N ₂ , flow rate 10 psi; auxiliary gas N ₂ , flow rate 1 psi; collision gas (CID) ) Ar at a pressure of 1.5 mTorr. The mass spectrometry scanning method is selected reaction monitoring (SRM), and positive ion detection is adopted. The internal standard (internal standard) was acetonitrile solution containing 0.2 μg/mL of aconitine, the lower limit of quantitation was 5 ng/mL, and the correlation coefficient was >0.99.

1. Metabolism research in vitro Verapamil was used as a reference to verify the detection system, agomelatine (abbreviated as Ago) and d3 -agomelatine (abbreviated as d3 -Ago) were used as references, and human liver microsomes In the in vitro test of the incubation system, the rate of decrease in the concentration of the compounds in each example was observed, and the metabolic stability in vitro was evaluated.

Precisely weigh about 10 mg of various samples to be tested, dissolve in 0.1 mL of DMSO, and dilute step by step with pure water to form 10 μM and 1 μM standard stock solutions. Operate on ice, and prepare the detection incubation system according to Table 4. Add NADPH to the incubation system to start the reaction, immediately take 50 μL in 150 μL acetonitrile as the zero time sample and 1 μM standard curve sample. Another 1 μM standard stock solution was added to the incubation system, and 50 μL was immediately taken in 150 μL acetonitrile as a 0.1 μM calibration sample. The remaining system was placed in a water bath at 37°C, and 50 μL was taken in 150 μL acetonitrile at 5 minutes, 15 minutes, 30 minutes, 1 hour, and 2 hours, respectively. Each sample was shaken and centrifuged at 18,000 g for 10 minutes, and the supernatant was taken for LC/MS/MS injection for determination. See Table 5 below for the experimental data and results of some of the compounds in the examples, and see Figure 2 for the graphical results.

Table 4. The composition of the incubation system

Table 5. Concentrations of test compounds measured at each time point (μM)

The metabolism of verapamil proves that the detection system is normal; the results of the control and the examples show that the compound metabolizes rapidly in the human liver microsomes, and is lower than the minimum detection limit after 60 minutes; the metabolic stability of the example compounds is stronger than that of the control The compound agomelatine and d3 -agomelatine; the compound of Example 1 has the highest metabolic stability.

2. Research on metabolism in vivo Taking agomelatine as a control, the pharmacokinetic parameters such as the exposure of the plasma concentration of the compound of Example 1 and the control drug were compared through rat oral/tail vein injection model tests, and the metabolic stability in vivo was evaluated. .

Preparation of intravenous administration solution: Accurately weigh about 5 mg of each test drug, dissolve it in 50 μL DMSO, and then add an appropriate amount of 40% PEG400 aqueous solution to prepare a 0.5 mg/mL solution. The administration volume is 0.2 mL/200g body weight, and the dose is 0.5 mg/kg body weight in terms of concentration conversion.

Solution preparation for intragastric administration: Accurately weigh about 5 mg of each test drug, suspend and disperse with 1% HPMC aqueous solution, and prepare a 1 mg/mL suspension. The administration volume is 1mL/200g body weight, and the dose is 5mg/kg body weight in terms of concentration conversion.

Rats were randomly divided into 4 groups, 5 in each group. Oral gavage and tail vein administration were carried out respectively according to the above doses. At 2 minutes, 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, and 3 hours after administration, blood was collected from the orbit, centrifuged at 8,000 rpm for 10 minutes, and 50 μL of plasma was taken, and 50 μL of internal standard, 150 μL of acetonitrile, and shaken to mix Evenly, centrifuge at 18,000 rpm for 10 minutes, and take the supernatant for LC/MS/MS sampling. The DAS pharmacokinetic program was used to analyze the measured data and calculate the main pharmacokinetic parameters. The experimental results are shown in Table 6 below.

Table 6 The main pharmacokinetic parameters after oral administration or tail vein injection in rats.

The results showed that compared with oral administration of agomelatine in rats, the plasma exposure AUC (0-t) of Example 1 was significantly increased (248.8 Vs 51.6), and the bioavailability was significantly increased (50.90% Vs 5.05%).

Part Four: Animal Behavior Studies of Example Compounds

1 , behavioral hopelessness model

Animals: Kunming mice, male, weighing 18-22g, SPF grade; SD rats, male, weighing 150-180g, SPF grade. The experiment was carried out after adaptive feeding, and fasted for 12 hours before the experiment.

All experimental administrations were suspended and dispersed with 1% hydroxypropylmethylcellulose (HPMC) aqueous solution, and shaken well before use. A blank control group (control), a positive drug group (agomelatine) and an experimental group (Examples 1, 2, 3, 4, 5) were set up. The dosage was 10mg/kg. The administration concentration and administration volume refer to the literature J Psychiatry Neurosci 2004;29(2):126-133. Mice are administered by intraperitoneal injection, and the administration volume is 0.5mL/20g; rats are administered by intragastric administration, and the administration volume is 2mL/100g.

1.1 Tail Suspension Experiment of Mice Mice were randomly divided into groups according to weight balance. Intraperitoneal injection was administered for three consecutive days, once a day, and the tail suspension test was performed 30 minutes after administration on the third day. The tail suspension box is 25×25×35 cm, and the center rope of the top plate is connected with a small clip. Adhesive tape is attached to the tail end of the mouse at 2 cm, and the tape is clamped with the clip, so that the mouse is in an upside-down position, observed for 6 minutes, and recorded. 4 minutes of cumulative immobility time. The results are shown in Table 7.

注：n=10，*P＜0.05　**P＜0.01　***P＜0.001與對照組比較Table 7 Tail Suspension Experiment Results of Mice for Compounds (10mg/kg)

Note: n=10, *P<0.05 **P<0.01 ***P<0.001 compared with the control group

1.2 Mice forced swimming test The animal grouping and drug administration method were the same as the tail suspension test of mice. Put the mice into a circular glass container with a height of 20 cm, an inner diameter of 12 cm, a water depth of 10 cm, and a water temperature of 25°C, observe for 6 minutes, and record the cumulative immobility time of the last 4 minutes. The results are shown in Table 8.

注：n=10，*P＜0.05　**P＜0.01　***P＜0.001與對照組比較Table 8 Compound (10mg/kg) mice forced swimming test results

Note: n=10, *P<0.05 **P<0.01 ***P<0.001 compared with the control group

1.3 Forced swimming test in rats Rats were randomly divided into groups according to weight balance. Administration was administered by intragastric administration for three consecutive days, once a day, and a forced swimming test was performed 1 hour after administration on the third day. Rats were placed in a circular glass tank with a height of 40 cm, an inner diameter of 18 cm, a water depth of 23 cm, and a water temperature of 25°C for 6 minutes, and the immobility time was accumulated within 5 minutes after recording. The results are shown in Table 9.

注：n=8，*P＜0.05　**P＜0.01　***P＜0.001與對照組比較Table 9 Compound (10mg/kg) Rat Forced Swimming Test Results

Note: n=8, *P<0.05 **P<0.01 ***P<0.001 compared with the control group

In the behavioral hopelessness model, Example 1 had the best antidepressant efficacy.

2 , rat model of chronic unpredictable stress

Animals: SD rats, male, weighing 150-180g, SPF grade.

Drug preparation and administration method: all experimental administrations were suspended and dispersed with 0.5% CMC-Na aqueous solution, and shaked well before use. Intragastric administration, the administration volume is 10mL/kg.

Set up a normal control group (no pressure, control), a stress model group (stress), a positive drug group (stress + agomelatine, 10/20/40 mg/kg) and an experimental group (stress + Example 1, 5 /10/20/40 mg/kg).

See Figure 3 for the experimental procedure. Rats were fed for 3 days after they were purchased, and then 48 hours of sucrose training (Sucrose training). After the training, a sucrose baseline test (Sucrose baseline test) was performed, and the rats were randomly and evenly divided into groups according to the degree of sucrose preference. Then (day 1, d1) a 4-week chronic unpredictable stress (CUS) program was carried out, and the stress methods were as follows: ① food deprivation (fasting); ② water deprivation; ③ strobe light; ④ overnight lighting ; ⑤ wet feeding (200 ml water added to 150 g litter); ⑥ noise stimulation (110 dB), 1 hour; ⑦ cold water swimming (water temperature l0 ℃); 1 cm from the root of the tail (clamping) for 6 minutes; ⑩ brake for 1 to 2 hours. One of the above stress methods was randomly used every day, but water deprivation and food fasting were separated, and corresponding drugs (including blank control group and positive drug group) were given 1 hour before stress every morning. Behavioral testing was performed after the end of chronic stress. On the 25th day (d25), the sucrose preference experiment (Sucrose preference); on the 28th day (d28), the open-field experiment (Open-field); on the 31st day (d31), the novelty-suppressed feeding test (Novelty-suppressed feeding test).

2.1 Rats in the sucrose preference experiment were fed adaptively for 3 days after purchase, and then 48 hours of sucrose drinking training: fasting and water deprivation, only 1% sucrose water was given for the first 24 hours, and 1% sucrose water and tap water were given simultaneously for the next 24 hours Conduct training; after the training, feed with normal water for 3 days, and measure the baseline of sucrose drinking water: fast for 14 hours, let the rats drink two different bottles of water freely, one of which is 1% sucrose water, and the other is tap water , respectively measure the drinking volume (g) of the two bottles of water within 1 hour, and calculate the sucrose preference. Sucrose preference (%) = drinking amount of sucrose water / (drinking amount of sucrose water + drinking amount of tap water) × 100%. On the 25th day of the stress program, the sucrose preference experiment was carried out again in the same way, and the sucrose preference degree was calculated.

注：n=9-12, *** P＜0.001，** P＜0.01與模型組比較，^# P＜0.05，與對照組比較。Table 10 Effect of Example Compound 1 on Sucrose Preference in Chronic Stress Rats

Note: n=9-12, *** P<0.001, ** P<0.01 compared with the model group, ^# P<0.05 compared with the control group.

2.2 On the 28th day of the rat open space activity test stress program, put the rat in the middle of the open box, put a 60 W light bulb at 45 cm directly above it for illumination, and observe the rat's activity within 5 minutes, including the level The number of crossing grids (the number of times more than three claws stepped into the adjacent grid), the number of vertical standing (the number of times the two forelimbs are more than 1 cm above the ground). Note: The experimental testing environment should be kept as quiet as possible; the rats should be put in from the same position and direction each time; the animal excrement should be cleaned up after each experiment.

注：n=9-12, **P＜0.01，*** P＜0.001，與模型組比較，^### P＜0.001，與對照組比較。Table 11 Effect of Example Compound 1 on Open Space Mobility of Chronic Stressed Rats

Note: n=9-12, **P＜0.01, ***P＜0.001, compared with the model group, ^### P＜0.001, compared with the control group.

2.3 Novelty-inhibiting feeding test stress program for rats On the 29th day, the rats were fasted for 48 hours (without water) and then subjected to the novelty-inhibiting feeding test (day 31, d31). Spread 2 cm thick sawdust, and place 12 food pills of the same size in the center. Putting in and calculating the latency period of rats starting to eat within 5 minutes at the same time, the criterion of food intake is that the animal starts to chew the food, rather than just sniffing or fiddling with the food. For rats that have not eaten for 5 minutes, the feeding latency is recorded as 5 minutes. The experimental testing environment should be kept as quiet as possible; the rats should be put in from the same position and direction each time; the experimental testing environment is preferably different from the breeding environment, and the light intensity of the testing environment is greater than that of the breeding environment.

注：n=9-12, **P＜0.01，與對照組比較，^# P＜0.05，^## P＜0.01，^### P＜0.001與模型組比較。Table 12. Effect of Example Compound 1 on Novelty Inhibition Ingestion Latency in Chronic Stressed Rats

Note: n=9-12, **P<0.01, compared with the control group, ^# P<0.05, ^## P<0.01, ^### P<0.001 compared with the model group.

In the chronic mild stress model, Example 1 can increase the sucrose preference of stressed rats, increase the number of horizontal crossings and vertical standing times, and shorten the feeding latency period, which proves that it has an antidepressant effect, and its drug effect is stronger than that of Agome Latin.

3. Anxiety Behavior Model of Rats with Repeated Dosing The requirements for experimental animals, drug preparation and administration are the same as those of the rat chronic mild stress model.

Instruments: Rat Vogel Drinking Anxiety Apparatus and Rat O-maze Apparatus are both produced by Shanghai Xinruan Company. The rat feeding box is a self-made white plastic box (60´45´25cm).

Randomly divided into groups, set up a blank control group (control), a positive drug group (agomelatine 10/20/40 mg/kg), and an experimental group (Example 1, 5/10/20/40 mg/kg). The drug was administered by gavage continuously once a day, and the novelty-inhibited feeding test, Vogel drinking conflict test, and O-maze test were carried out on different days. All behavioral experiments were carried out at 9:00-12:00, and the administration time was 16:00-17:00. The experimental procedure is as follows: D12, novelty inhibition feeding test (animals were fasted for 48 hours before the experiment); D18, Vogel water conflict test (animals were deprived of water for 48 hours before the experiment); D21, O-maze experiment.

3.1 Novelty-inhibited feeding experiment for rats The floor of the rat feeding box was covered with ordinary litter with a thickness of 1.5 cm, and 6 pieces of ordinary block-shaped rat feed of equal size were placed in the center. During the experiment, the rats were put into the feeding box from a certain fixed position, timed and observed for 5 minutes, and the time from when the rats entered the box to when they began to chew and chew the feed was recorded with a stopwatch.

注：n=9-12,*P＜0.05，**P＜0.01，***P＜0.001與對照組比較。Table 13. Effect of Chronic Administration of Example Compound 1 on Novelty Inhibition Ingestion Latency in Rats

Note: n=9-12, *P<0.05, **P<0.01, ***P<0.001 compared with the control group.

3.2 Rat Vogel drinking conflict experiment Rat Vogel drinking anxiety instrument connects the water bottle mouth, electric grid and the current loop of the control instrument through the animal body when the rat drinks water, and the control instrument can automatically record the number of times the animal drinks water and deliver the plantar electric shock . After the rats were deprived of water for 48 hours, they were put into the test box alone. When the animals drank 20 times in the test box, the controller started to count for 3 minutes, and every time the rats drank 20 times, a plantar electric shock (0.35mA, continuous 2s), the instrument automatically records the number of times the rat is shocked to drink water within 3 minutes.

注：n=9-12,*P＜0.05，**P＜0.01，***P＜0.001與對照組比較。Table 14. Effect of Chronic Administration of Example Compound 1 on Vogel Shock Conflict Drinking Behavior of Rats

Note: n=9-12, *P<0.05, **P<0.01, ***P<0.001 compared with the control group.

3.3 Rat O- maze experiment The O-maze apparatus was placed in the center of a dark room and illuminated by infrared lamps during the experiment. Place the animal in the center of the closed arm of the O-maze track, time it for 5 minutes, and monitor the activity of the rat in the maze with an infrared camera. Animals in each group were given a single intragastric administration 60 minutes before the experiment. The observation indicators were the number of times the rats entered the open arm and the cumulative residence time in the open arm.

注：n=9-12, *P＜0.05，**P＜0.01，*** P＜0.001，與對照組比較。Table 15 Effect of Long-term Administration of Example Compound 1 on O-maze Behavior of Rats

Note: n=9-12, *P<0.05, **P<0.01, ***P<0.001, compared with the control group.

In the anxiety behavior model of rats administered repeatedly, Example 1 can reduce the feeding latency of anxiety model rats, increase the frequency of electric shock drinking, and increase the exploration behavior of opening arms in the O-maze, which proves that it has an anxiolytic effect, and the drug effect stronger than agomelatine.

Part V: Preliminary Safety Evaluation of Example Compounds The requirements for experimental animals are the same as those in Part IV "Behavioral Research/Behavior Despair Model". Taking agomelatine as the control drug, the safety of single administration was preliminarily judged.

1. Acute Toxicity Experiment in Mice Mice were randomly divided into groups of 10 mice according to body weight, and a group of Example 1, a agomelatine control group and a blank control group were set up. Intragastric administration, the dosage is 5000mg/kg and 2000mg/kg. The drug is dispersed with 1% hydroxypropylmethylcellulose (HPMC) aqueous solution, and the administration volume is calculated according to 0.2mL/10g. Sacrifice after 14 days of observation after administration.

Example 1, 5000mg/kg group: 15 minutes after the administration, they fell into a coma, and all woke up and returned to normal within 24 hours. There was no adverse reaction 14 days after the administration, and the diet and behavior were normal. There was no significant difference between the body weight and the blank group.

Example 1, 2000 mg/kg group: after administration, the amount of activity slightly decreased but there was no obvious adverse reaction. There was no adverse reaction 14 days after the administration, and the diet and behavior were normal. There was no significant difference between the body weight and the blank group.

Agomelatine, 5000mg/kg group: All fell into a coma 15 minutes after administration, and died one after another 12 hours later.

Agomelatine, 2000mg/kg group: 15 minutes after administration, all fell into a coma, and 4 died within 12 hours, and the others all woke up and returned to normal within 24 hours. There was no obvious adverse reaction 14 days after the administration, and the diet and behavior were normal. Compared with the blank group, the body weight was significantly lighter on the 1st and 2nd day after administration, and returned to normal on the 7th and 14th day.

Results: On the mouse model, Example 1 is safer than the control drug agomelatine.

2. Acute Toxicity Test in Rats Rats were randomly divided into groups of 10 rats according to their body weight. Group 1 of Example, agomelatine control group and blank control group were set up. Intragastric administration, the dosage is 2000mg/kg. The drug was dispersed with 1% hydroxypropylmethylcellulose (HPMC) in water. Sacrifice after 14 days of observation after administration.

Example 1, 2000 mg/kg group: after administration, the amount of activity slightly decreased but there was no obvious adverse reaction. There was no adverse reaction 14 days after the administration, and the diet and behavior were normal. There was no significant difference between the body weight and the blank group.

Agomelatine, 2000mg/kg group: 8 animals slowed down or fell into lethargy 15 minutes after administration, and all returned to normal within 2 hours. There was no adverse reaction 14 days after the administration, and the diet and behavior were normal. There was no significant difference between the body weight and the blank group.

Results: On the rat model, Example 1 is safer than the comparison drug agomelatine.

The sixth part: 1000 tablet preparations of the pharmaceutical composition containing the embodiment compound , each tablet contains 10mg dose, and its formula is as follows:

It should be noted that the technical features in the embodiments of the present application can be used in any combination if there is no conflict.

Although the specific implementations of the present invention have been described in detail, those skilled in the art will understand that various modifications and substitutions can be made to those details according to all the teachings that have been disclosed, and these changes are all within the protection scope of the present invention. The scope of protection of the present invention is given by the appended claims and any equivalents thereof.

none.

Figure 1 shows the results of MT1, MT2 and 5HT _2c receptor binding experiments of the compounds of Example 1 and Example 4 and the control Ago. Fig. 2 shows the in vitro metabolic stability test results of the compounds of Examples 1, 2, 3, 4, 5, 6, and 7 and the control Ago and d3-Ago. Figure 3 shows the chronic stress protocol in rats.

Claims (11)

A compound of formula I or a pharmaceutically acceptable salt, solvate or mixture thereof,

Wherein: X is fluorine or chlorine; R ₁ is CH ₃ or CD ₃ ; R ₂ is CH ₃ or C ₂ H ₅ ; the condition is that the compound of formula I does not include N-(2-(6-fluoro-7-methoxy base-naphthalen-1-yl)ethyl)acetamide. According to the compound of formula I or the pharmaceutically acceptable salt, solvate or mixture thereof according to claim 1, wherein: said R ₁ is CD ₃ . According to the compound of formula I of item 1 of the scope of application for patents or a pharmaceutically acceptable salt, solvate or mixture thereof, it is selected from: N-(2-(6-chloro-7-deuteromethoxy -Naphthalen-1-yl)ethyl)acetamide; N-(2-(6-chloro-7-methoxy-naphthalen-1-yl)ethyl)acetamide; N-(2-(6 -Fluoro-7-deuteromethoxy-naphthalen-1-yl)ethyl)acetamide; N-(2-(6-chloro-7-deuteromethoxy-naphthalen-1-yl)ethyl ) propionamide; N-(2-(6-chloro-7-methoxy-naphthalen-1-yl) ethyl) propionamide; N-(2-(6-fluoro-7-methoxy-naphthalene-1-yl)ethyl)propionamide; N-(2-(6-chloro-7-deuteromethoxy-naphthalene-1 -yl)ethyl)acetamide hydrogen chloride hydrate; N-(2-(6-chloro-7-deuteromethoxy-naphthalen-1-yl)ethyl)acetamide hydrogen chloride; N-( 2-(6-Chloro-7-methoxy-naphthalene-1-yl)ethyl)acetamide hydrochloride hydrate; N-(2-(6-chloro-7-methoxy-naphthalene-1- Base) ethyl) acetamide hydrogen chloride salt; N-(2-(6-chloro-7-methoxy-naphthalen-1-yl) ethyl) acetamide hydrogen bromide hydrate; N-(2 -(6-Chloro-7-methoxy-naphthalen-1-yl)ethyl)acetamide sulfate; N-(2-(6-chloro-7-methoxy-naphthalen-1-yl)ethyl base) acetamide methanesulfonate; and N-(2-(6-fluoro-7-methoxy-naphthalen-1-yl)ethyl)acetamide hydrogen chloride hydrate. A pharmaceutical composition comprising: i) a therapeutically and/or preventively effective amount of the compound of formula I according to any one of item 1 to item 3 of the patent application or a pharmaceutically acceptable salt thereof, and a solvent compounds or their mixtures; and ii) pharmaceutically acceptable auxiliary materials. A pharmaceutical combination comprising: a) one or more first active ingredients selected from the compound of formula I according to any one of item 1 to item 3 of the patent application and its pharmaceutically acceptable salts and solvents compounds or mixtures thereof; and b) one or more other active ingredients selected from melatonin receptor agonists and 5-HT _2C receptor antagonists. A use of a compound of formula I or a pharmaceutically acceptable salt, solvate or mixture thereof according to any one of items 1 to 3 of the patent application, which is used to prepare melatonin receptor agonist. A use of a compound of formula I or a pharmaceutically acceptable salt, solvate or mixture thereof according to any one of the first to third items of the scope of application for the preparation of 5-HT _2C receptor antagonist. A use of a compound of formula I or a pharmaceutically acceptable salt, solvate or mixture thereof according to any one of the first to third items of the patent application scope, which is used for the preparation of prophylactic or therapeutic Drugs for diseases or conditions selected from the group consisting of melatoninergic disorders, nervousness, anxiety disorders, seasonal affective disorder, cardiovascular disorders, digestive disorders, schizophrenia, phobias, depression, major depressive disorders, Sleep disorders, sleep disorders, insomnia or fatigue due to jet lag, weight disorders. A method for synthesizing the compound of formula I in item 1 of the scope of the patent application, which comprises: making a Friedel-Crafts reaction between halogen ortho-substituted methoxybenzene and succinic anhydride under the action of a catalyst to obtain an aromatic ketone intermediate

, where X is fluorine or chlorine; R ₁ is CH ₃ or CD ₃ ; the ketone carbonyl in the aromatic ketone intermediate is reduced to methylene with triethylsilane to obtain the aromatic butyric acid intermediate

; The aromatic butyric acid intermediate is cyclized under the action of an acidic catalyst to obtain a tetralin intermediate

; Tetralin intermediate and cyanoacetic acid generation cyanation reaction obtains dihydronaphthyl acetonitrile intermediate

; Dihydronaphthyl acetonitrile intermediate dehydrogenation obtains naphthyl acetonitrile intermediate

and naphthyl acetonitrile intermediate reacts with sodium borohydride and acetic anhydride or propionic anhydride in the presence of catalyst hexahydrate nickel chloride to obtain the compound of formula I. According to the method of item 9 of the scope of patent application, it also includes: dissolving the compound of formula I in toluene and reacting with anhydrous aluminum trichloride to obtain naphthol; and reacting the naphthol with deuterated methyl iodide to obtain deuterated formula I compound. According to the method of claim 9 or claim 10, it also includes: reacting the compound of formula I with an acid to form a salt.

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